Selective synthesis of 2-pyridones and pyrimidine-2,4-diones by neutral rhodium(I) complex-catalyzed cyclocotrimerization of alkynes and isocyanates

Article abstract of DOI:10.1016/j.tetlet.2006.07.105

A neutral rhodium(I) complex, 'RhCl(PPh₃)₂' generated by the combination of [RhCl(C₂H₄)₂]₂ with a fourfold amount of PPh₃, effectively catalyzed the cyclocotrimerization of alkyn

Full text of DOI:10.1016/j.tetlet.2006.07.105

Tetrahedron Letters 47 (2006) 7107–7111
Selective synthesis of 2-pyridones and pyrimidine-2,4-diones
by neutral rhodium(I) complex-catalyzed cyclocotrimerization
of alkynes and isocyanates
Teruyuki Kondo,* Masato Nomura, Yasuyuki Ura, Kenji Wada and Take-aki Mitsudo
Department of Energy and Hydrocarbon Chemistry, Graduate School of Engineering, Kyoto University,
Nishikyo-ku, Kyoto 615-8510, Japan
Received 14 June 2006; revised 10 July 2006; accepted 13 July 2006
Available online 8 August 2006
Abstract—A neutral rhodium(I) complex, ‘RhCl(PPh3)2’ generated by the combination of [RhCl(C2H4)2]2 with a fourfold amount of
PPh3, effectively catalyzed the cyclocotrimerization of alkynes (1) and isocyanates (2) to give 2-pyridones (3) and/or pyrimidine-2,4-
diones (4), selectively, by controlling the molar ratio of alkynes (1) and isocyanates (2).
Ó 2006 Elsevier Ltd. All rights reserved.
Many naturally occurring and synthetic compounds
containing the 2-pyridone scaffold possess interesting
pharmacological properties.1 Recent interest in the 2-
pyridone ring system has led to several new procedures
for its preparation.2 A highly convergent and atom-eco-
nomical approach is the transition metal complex-cata-
lyzed cyclocotrimerization of two alkynes with an
isocyanate.3 Since this methodology was first reported
independently by Yamazaki using cobalt catalysts4 and
by Hoberg using nickel catalysts,5 a remarkable progress
has been made with these catalysts.6,7 On the other
hand, Takahashi succeeded in preparing various 2-
pyridones from two different internal alkynes and an
isocyanate via the formation of an azazirconacyclopen-
tenone intermediate, followed by transmetallation with
Ni(PPh3)2Cl2; however this reaction requires stoichio-
metric amounts of both Ni and Zr complexes.8 Recently,
Itoh developed the first ruthenium-catalyzed synthesis
of bicyclic 2-pyridones by the partial intermolecular
cycloaddition of diynes with isocyanates.9
and isocyanates has thus far been investigated by only
two research groups. Flynn reported that 1-(4-chloro-
phenyl)-3,5-dimethoxycarbonyl-4,6-dimethylpyrid-2-one
was obtained in only 13% yield when a rhodacyclic
complex was used as a neutral rhodium catalyst for
the cyclocotrimerization of methyl tetrolate with 4-
chlorophenylisocyanate.10 Tanaka reported the chemo-,
regio-, and enantioselective cycloaddition of diynes
or terminal alkynes with isocyanates to give 2-pyridones
catalyzed by
a cationic rhodium complex, [Rh-
(cod)2]BF4, with H8-BINAP.11 Since various neutral
rhodium complexes are highly effective for cyclotrimer-
ization and related reactions of alkynes,12,13 we reinves-
tigated the catalytic activities of several neutral rhodium
complexes combined with phosphine ligands in detail.
We report here that a neutral rhodium(I) complex,
‘RhCl(PPh3)2’ generated by the combination of
[RhCl(C2H4)2]2 with a fourfold amount of PPh3, effec-
tively catalyzed the cyclocotrimerization of alkynes
and isocyanates to give 2-pyridones and/or pyrimidine-
2,4-diones, selectively, by controlling the molar ratio
of alkynes and isocyanates. Another advantage of
the present rhodium-catalyzed cyclocotrimerization of
alkynes and isocyanates is stability of the catalyst as
compared to the reported cationic rhodium11 and nick-
el(0)5 catalysts.
Notably, there has been much less progress in the devel-
opment of rhodium catalysts compared to cobalt and
nickel catalysts. To the best of our knowledge, the rho-
dium complex-catalyzed cyclocotrimerization of alkynes
Keywords: Ruthenium; Catalyst; Cyclocotrimerization; 2-Pyridone;
Pyrimidine-2,4-dione.
First, the catalytic activities of several rhodium as well
as ruthenium complexes14 were examined in the synthe-
sis of 3,4,5,6-tetraethyl-1-phenyl-2-pyridone (3a) by the
*
Corresponding author. Tel.: +81 75 383 2508; fax: +81 75 383
2510; e-mail: teruyuki@scl.kyoto-u.ac.jp
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.07.105

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T. Kondo et al. / Tetrahedron Letters 47 (2006) 7107–7111
cyclocotrimerization of 3-hexyne (1a) and phenyl iso-
cyanate (2a) (Eq. 1).
(2.0 ml) at 120 °C for 12 h under an argon atmosphere,
the corresponding 2-pyridone, 3,4,5,6-tetraethyl-1-
phenyl-2-pyridone (3a), was obtained in 60% yield (iso-
lated yield, 50%; entry 2).15
O
Rh catalyst
Ph
Et
Et
Et
0.025 mmol
N
+
2 Et
Et
Ph N C O
mesitylene 2.0 ml
120 oC, 12 h
The results obtained from the reaction of several iso-
cyanates with 3-hexyne (1a) under optimum reaction
conditions are summarized in Table 2. Both aromatic
and aliphatic isocyanates were readily converted into
the corresponding 2-pyridones. No significant effect
was observed for the electron-donating (p-Me (2b))
and electron-withdrawing substituents (p-Cl (2c)) on a
phenyl ring in aromatic isocyanates. The reactions of
n-hexyl isocyanate (2d) and cyclohexyl isocyanate (2e)
with 3-hexyne (1a) gave the corresponding 2-pyridones,
3d and 3e, in isolated yields of 56% and 34%, respec-
tively, while more bulky aliphatic isocyanates, such as
tert-butyl isocyanate (2f) and adamantyl isocyanate
(2g), could not be used in the present reaction. As for
alkynes, 4-octyne (1b) was applicable to give the corre-
sponding 2-pyridone (3f) in an isolated yield of 30%,
while no 2-pyridones were obtained from the reactions
of diphenylacetylene (1c), 1-phenyl-1-propyne (1d) or
dimethyl acetylenedicarboxylate (1e) with phenyl iso-
cyanate (2a).
1a 5.0 mmol
2a 1.0 mmol
3a
Et
ð1Þ
Among the catalysts examined, RhCl(CO)(PPh3)2 (3a
23%), [RhCl(CO)2]2 (3a 11%), and [RhCl(C2H4)2]2 (3a
10%) as well as RhCl(PPh3)3 (3a 44%) were effective.
However, ruthenium complexes, such as RuCl2(PPh3)3,
CpRuCl(PPh3)2 [Cp = cyclopentadienyl], Cp*RuCl(cod)
[Cp* = pentamethylcyclopentadienyl, cod = 1,5-cyclo-
octadiene], and [RuCl2(CO)3]2, were totally ineffective.
The effect of phosphine ligands was examined in the
[RhCl(C2H4)2]2-catalyzed synthesis of 3a from 1a and
2a. As shown in Table 1, the concomitant use of PPh3
ligand as well as its amount relative to [RhCl(C2H4)2]2
catalyst are highly important for the present reaction
(entries 1–3). The use of two equivalents of PPh3 per rho-
dium atom (i.e., [RhCl(C2H4)2]2 (0.025 mmol) and PPh3
(0.10 mmol)) gave the best result (3a, 60%), which sug-
gests that the catalytically active rhodium species would
be a coordinatively unsaturated (14e) and sterically less
hindered ‘RhCl(PPh3)2’. In contrast, catalyst systems
combined with other monodentate phosphines, such as
P(C6H4Me-p)3, P(C6H4F-p)3, PCy2Ph, PCy3 [Cy =
cyclohexyl], and PnBu3, as well as bidentate phosphines,
such as 1,4-bis(diphenylphosphino)butane (dppb) and
1,10-bis(diphenylphosphino)ferrocene (dppf), gave 3a in
moderate to poor yields (entries 4–10). Consequently,
when the reaction of 3-hexyne (1a, 5.0 mmol) with
phenyl isocyanate (2a, 1.0 mmol) was carried out in
the presence of a catalytic amount of [RhCl(C2H4)2]2
(0.025 mmol) and PPh3 (0.10 mmol) in mesitylene
On the other hand, treatment of alkynes (1) with a large
excess amount of isocyanates (2, 20 equiv)16 under the
same catalytic reaction conditions gave pyrimidine-2,4-
diones (4) in high yields, which were obtained by the
cyclocotrimerization of two isocyanates with an alkyne
(Eq. 2).
[RhCl(C2H4)2]2
0.013 mmol
PPh3
0.050 mmol
O
R'
R'
N
N
+
R
R
2 R' N C O
mesitylene 1.0 ml
120 oC, 12 h
R
O
1 0.50 mmol
2 10.0 mmol
R
4
ð2Þ
The results obtained from the cyclocotrimerization of
alkynes (1a, 1c, and 1d, 0.50 mmol) and n-hexyl isocya-
nate (2d, 10 mmol) in the presence of a catalytic amount
of [RhCl(C2H4)2]2 (0.013 mmol) and PPh3 (0.050 mmol)
in mesitylene (1.0 ml) at 120 °C for 12 h under an argon
atmosphere are summarized in Table 3. For example,
5,6-diethyl-1,3-dihexyl-1,3-dihydropyrimidine-2,4-dione
(4a) was obtained from 1a and 2d in an isolated yield of
86% (entry 1). No 2-pyridone was obtained at all, as
confirmed by careful GC–MS analysis. In contrast to
the synthesis of 2-pyridones, diphenylacetylene (1c)
and 1-phenyl-1-propyne (1d) can be used in the present
reaction (entries 2 and 3).
Table 1. The effect of phosphine ligands in the [RhCl(C2H4)2]2-
catalyzed synthesis of 3a from 1a and 2aa
Entry
Ligand
Yield of 3ab (%)
1
2
3c
4
—
PPh3
PPh3
P(C6H4Me-p)3
P(C6H4F-p)3
PCy2Ph
PCy3
PnBu3
dppb
10
60
40
7
33
14
22
23
32
27
5
6d
7d
8
9e
10f
dppf
a 3-Hexyne (1a) (5.0 mmol), phenyl isocyanate (2a) (1.0 mmol),
[RhCl(C2H4)2]2 (0.025 mmol), phosphine (0.10 mmol as a P atom),
and mesitylene (2.0 ml) at 120 °C for 12 h under an argon
atmosphere.
Considering the results obtained above, the most plausi-
ble mechanism is illustrated in Scheme 1. We now be-
lieve that an azarhodacyclopentenone derived from the
oxidative cyclization of an alkyne (1) and an isocyanate
(2) on an active rhodium center is the key intermediate
for the present reaction.17 Since cocyclization of 1,6-
heptadiyne (5a) and phenyl isocyanate (2a) did not
proceed at all by the present catalyst system,9a,b the
b GLC yield.
c PPh3 (0.15 mmol) was used.
d Cy = cyclohexyl.
e 1,4-Bis(diphenylphosphino)butane.
f 1,10-Bis(diphenylphosphino)ferrocene.

T. Kondo et al. / Tetrahedron Letters 47 (2006) 7107–7111
7109
Table 2. [RhCl(C2H4)2]2/PPh3-catalyzed synthesis of 2-pyridones (3) from 3-hexyne (1a) with isocyanates (2)a
Entry
Isocyanate
Product
Isolated yield (%)
O
50 (60)b
N C O
2a
Et
Et
1
N
3a
Et
Et
Me
Cl
O
Et
Et
Me
Cl
N C O
N
2
3
3b
59
63
2b
2c
Et
Et
O
Et
N C O
N
3c
Et
Et
Et
O
n
-C6H13
Et
Et
n
-C6H13 N C O
N
4
3d
56
34
2d
Et
Et
O
Et
N C O
N
5c
3e
Et
Et
2e
Et
a 3-Hexyne (1a) (5.0 mmol), isocyanate (2) (1.0 mmol), [RhCl(C2H4)2]2 (0.025 mmol), PPh3 (0.10 mmol), and mesitylene (2.0 ml) at 120 °C for 12 h
under an argon atmosphere.
b GLC yield.
c For 26 h. Cyclohexyl isocyanate was recovered in 58%.
Table 3. [RhCl(C2H4)2]2/PPh3-catalyzed synthesis of pyrimidine-2,4-diones (4) from alkynes (1) with n-hexyl isocyanate (2d)a
Entry
Alkyne
Product
Isolated yield (%)
86
O
Et
Et
n
-C6H13
Et
C6H13
O
-
-
n
1
N
N
N
4a
4b
1a
Et
O
n
-C6H13
Ph
C6H13
O
n
n
Ph
Ph
N
N
2
62
1c
Ph
O
n
-C6H13
Ph
C6H13
O
-
-
N
N
4c
Ph
Me
Me
O
63b
63b
3
c
1d
(4c/4c'
= 4/1)
n
-C6H13
Me
C6H13
O
n
N
4c'
Ph
a Alkyne (1) (0.50 mmol), n-hexyl isocyanate (2d) (10.0 mmol), [RhCl(C2H4)2]2 (0.013 mmol), PPh3 (0.050 mmol), and mesitylene (1.0 ml) at 120 °C
for 12 h under an argon atmosphere.
b Determined by GLC and 1H NMR.

7110
T. Kondo et al. / Tetrahedron Letters 47 (2006) 7107–7111
O
O
R'
R
R
R
R
R'
R'
O
N
N
N
1
+
R
R
R' N C O
R
3
R
4
2
[RhI]
[RhI]
cycle A
cycle B
O
O
R'
R'
R'
R'
R
N
N
N
O
[RhIII]
R
[RhIII]
N
[RhIII]
O
R
R
R
R
R
R
R' N C O
R
R
1
2
Scheme 1. Possible mechanism for Rh-catalyzed synthesis of 2-pyridones 3 and pyrimidine-2,4-diones 4 from alkynes 1 and isocyanates 2.
mechanism involving a rhodacyclopentadiene derived
from the oxidative cyclization of two alkynes can be ru-
led out. In cycle A, an azarhodacycloheptadienone
could be formed by the selective insertion of an alkyne
into the rhodium–carbon bond in an azarhodacyclopen-
tenone,17 and the subsequent reductive elimination gives
2-pyridone (3). On the other hand, insertion of an iso-
cyanate in place of an alkyne into the rhodium–nitrogen
bond rather than the rhodium–carbon bond in an aza-
rhodacyclopentenone proceeded,18 when a large excess
amount of isocyanates was used, to give a diazarhoda-
cycloheptenedione, and subsequent reductive elimina-
tion gives pyrimidine-2,4-diones (4) according to cycle B.
Ministry of Education, Culture, Sports, Science and
Technology, Japan. T.K. acknowledges financial sup-
port from the Japan Chemical Innovation Institute. This
research (project) was conducted in part at the Ad-
vanced Research Institute of Environmental Material
Control Engineering, Katsura-Int’tech Center, Gradu-
ate School of Engineering, Kyoto University.
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2006.07.105.
In conclusion, we have developed a ‘neutral’ rhodium
complex-catalyzed cyclocotrimerization of alkynes and
isocyanates to 2-pyridones. Although Flynn10 and
Tanaka11 claimed that neutral rhodium complexes have
extremely low catalytic activity in the cyclocotrimeriza-
tion of alkynes and isocyanates, we found that a coord-
inatively unsaturated and sterically less hindered
‘RhCl(PPh3)2’ generated by the combination of [RhCl-
(C2H4)2]2 with a fourfold amount of PPh3 showed good
to high catalytic activity. In addition, the selective syn-
thesis of pyrimidine-2,4-diones in place of 2-pyridones
was realized by controlling the molar ratio of alkynes
and isocyanates.
References and notes
1. For a review, see: Rigby, J. H. Synlett 2000, 1–12.
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3. Varela, J. A.; Saa, C. Chem. Rev. 2003, 103, 3787–3801.
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Hong, P.; Yamazaki, H. Tetrahedron Lett. 1977, 18, 1333–
1336.
5. (a) Hoberg, H.; Oster, B. W. Synthesis 1982, 324–325; (b)
Hoberg, H.; Oster, B. W. J. Organomet. Chem. 1982, 234,
C35–C38; (c) Hoberg, H.; Oster, B. W. J. Organomet.
Chem. 1983, 252, 359–364.
6. For cobalt catalysts, see: (a) Earl, R. A.; Vollhardt, K. P.
C. J. Am. Chem. Soc. 1983, 105, 6991–6993; (b) Earl, R.
A.; Vollhardt, K. P. C. J. Org. Chem. 1984, 49, 4786–4800;
(c) Diversi, P.; Ingrosso, G.; Lucherini, A.; Malquori, S. J.
Mol. Catal. 1987, 40, 267–280.
7. For nickel catalysts, see: Duang, H. A.; Cross, M. J.;
Louie, J. J. Am. Chem. Soc. 2004, 126, 11438–11439, and
references cited therein.
Acknowledgements
This work was supported in part by Grants-in-Aid for
Scientific Research (B), Scientific Research on Priority
Areas, and the 21st-century COE program, COE for a
United Approach to New Materials Science, from the
Japan Society for the Promotion of Science and the

T. Kondo et al. / Tetrahedron Letters 47 (2006) 7107–7111
7111
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Y.; Yamanaka, M.; Nakajima, K.; Kotora, M. J. Am.
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2001, 3, 2117–2119; (b) Yamamoto, Y.; Kinpara, K.;
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theoretical study was also reported by Kirchner and co-
workers, see: (c) Schmid, R.; Kirchner, K. J. Org. Chem.
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M.; Mitsudo, T. Angew. Chem., Int. Ed. 2004, 43, 5369–
5372.
15. After the reaction of entry 2 in Table 1, phenyl isocyanate
(2a) still remained, however, longer reaction time did not
improve both the conversion of 2a and the yield of 3a. In
the present reaction, decarbonylation of isocyanates
occurred to some extent. The generated carbon monoxide
may coordinate to an active rhodium species leading to
deactivation of the rhodium catalyst, which accords well
with the low catalytic activity of RhCl(CO)(PPh3)2 (vide
supra).
10. Flynn, S. T.; Hasso-Henderson, S. E.; Parkins, A. W. J.
Mol. Catal. 1985, 32, 101–105.
11. Tanaka, K.; Wada, A.; Noguchi, K. Org. Lett. 2005, 7,
4737–4739.
12. Evans, F. A. Modern Rhodium-Catalyzed Organic
Reactions, 4th ed.; Wiley-VCH: Weinheim, 2003; pp
129–149.
16. Since the reactivity of an alkyne is higher than that of an
isocyanate under the present catalytic reaction conditions,
treatment of 3-hexyne (1a) with an equal amount of n-
hexyl isocyanate (2d) predominantly gave the correspond-
ing 2-pyridone (3d). In order to obtain pyrimidine-2,4-
dione (4a), a large excess amount (at least, 20 equiv) of n-
hexyl isocyanate (2d) is needed.
13. Most recently, the unusual [2+2+2] cocyclization of
alkenylisocyanates and alkynes via CO migration has
been reported by Rovis and co-workers, see: Yu, R. T.;
Rovis, T. J. Am. Chem. Soc. 2006, 128, 2782–2783.
14. Several rhodium and ruthenium complexes are highly
efficient catalysts for the ring-opening dimerization of
cyclobutenones via a heterocumulenic ‘vinylketene’ inter-
mediate. See: Kondo, T.; Taguchi, Y.; Kaneko, Y.; Niimi,
17. Hoberg and co-workers isolated the corresponding nick-
elacycles in the nickel-catalyzed cyclocotrimerization of
alkynes and isocyanates, in which the insertion of an
alkyne into the nickel–carbon bond rather than the nickel–
nitrogen bond in an azanickelacyclopentenone proceeded.
See: Ref. 5b and 5c.
18. For example, see: Rais, D.; Bergman, R. G. Chem. Eur. J.
2004, 10, 3970–3978.